Moderate to severe pain can be effectively treated with opioid analgesics such as hydrocodone. However since many opioids are habit forming, the risk of abuse can be moderated by combining the opioid with a non-opioid analgesic, e.g. acetaminophen or an NSAID such as, aspirin, ibuprofen, etc., thereby allowing effective pain management at lower doses of the opioid analgesic. However, the need to administer multiple dosage forms can result in problems such as patient compliance issues or dosage errors.
One approach to preventing such problems is to combine multiple analgesics (e.g., the combination of non-opioid and opioid analgesics) into a single dosage form in order to minimize the number of different dosage forms administered, and to ensure that the combination of analgesics are administered in the correct relative dosages. For example, Vicodin® is an immediate-release (IR) tablet containing 5 mg of hydrocodone bitartrate and 500 mg of acetaminophen, intended for the management of severe pain. However, it is very difficult to reproducibly prepare homogeneous blends of hydrocodone and acetaminophen at the required 1:100 weight ratio (e.g., with a content uniformity having an RSD of 6% or less as required by regulatory agencies worldwide). Thus, there is a need for methods for uniformly and reproducibly combining a high-dose of non-opioid analgesic and a low-dose opioid analgesic into a single dosage form.
The two most widely used types of oral dosage forms are tablets and capsules. However, such dosage forms have several disadvantages. For example, it is estimated that 50% of the population have problems swallowing tablets (see Seager, Journal of Pharmacol. and Pharm. 50, pages 375-382, 1998). It is especially hard for the elderly or for children to swallow tablets or capsules, or to medicate patients who are unable or unwilling to swallow tablets or capsules. Furthermore, conventional tablets or capsules usually must be administered with water, which is not always possible or convenient. This leads to poor or even non-compliance with the treatment which consequently has a negative impact on the efficacy of the treatment. Orally disintegrating tablet (ODT) dosage fauns have been introduced to address such problems, because ODTs rapidly dissolve or disintegrate in the buccal cavity and the resulting slurry or suspension of the drug is more readily swallowed by the patient. Such dosage forms are also more convenient because they need not be administered with water.
Because the ODT dosage form disintegrates in the oral cavity of the patient, the disintegrated ODT must be palatable. For example, if one or more of the analgesic drugs in the ODT are bitter tasting, the drug-containing particles comprising the ODT must be taste-masked, e.g., by coating the drug-containing particles with a polymeric membrane to prevent release of the drug in the oral cavity. However, the main drawback of taste-masking is slower dissolution of the drug(s) from effectively taste-masked microparticles. The more bitter the drug, the thicker the taste-masking coating required and hence, the slower the drug release from the taste-masked drug-containing particles. Thus the very process of effectively taste-masking the drug-containing particles results in a substantially slower drug release, with concomitant slower systemic absorption of the drug in the gastrointestinal tract.
In some cases, slower drug release is a particular problem for ODT dosage forms which are intended to be bioequivalent to a reference listed immediate-release (IR) dosage form of the drug, for example bioequivalent to conventional tablet or effervescent tablet based IR dosage foams having a Tmax, of less than an hour, and rapid-onset of action. For such bioequivalent immediate release ODT products, it is essential that the taste-masking layer should not substantially lower the release rate of the drug. For ODT compositions containing combinations of two or more analgesic drugs (e.g., a non-opioid/opioid analgesic formulation) this problem is particularly acute, because the different analgesic drug components of the combination ODT may require different levels of taste-masking depending on the degree of bitterness of the drugs (i.e., analgesics with low bitterness levels may require little or no taste-masking, while highly bitter analgesics may require substantial taste-masking layers). Adding further complication, taste-masking layers reduce the release rate of poorly soluble analgesic drugs more than for more soluble drugs. In certain cases, an ODT composition comprising taste-masked opioid analgesic particles combined with sustained release coated non-opioid analgesic particles may be more desirable.
In addition, ODTs must rapidly disintegrate on contact with the saliva in the oral cavity while also providing sufficient tablet hardness and strength sufficient to withstand attrition during packaging, storage, transportation, distribution, and end use, and also provide acceptable organoleptic properties (e.g., be palatable as described above, and exhibit a smooth (non-gritty) mouthfeel), and acceptable pharmacokinetic properties (i.e., rapid onset, Cmax, AUC properties similar to the reference listed drugs). Achieving all of these properties is often quite difficult because thicker taste-masking layers may be required for adequate taste-masking of more soluble and/or more bitter drugs, which may make it difficult to obtain the required rapid drug release.
Thus, the preparation of clinically effective pharmaceutical compositions comprising a non-opioid analgesic and an opioid analgesic, particularly in the form of an ODT, is quite difficult and requires the balancing of many different and often competing requirements.